Discovery of a potent Gilteritinib-based FLT3-PROTAC degrader for the treatment of Acute myeloid leukemia.
Bioorg Chem
; 149: 107477, 2024 Aug.
Article
de En
| MEDLINE
| ID: mdl-38820938
ABSTRACT
Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, B3-2 exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that B3-2 induced FLT3-ITD degradation in a ubiquitin-proteasome-dependent manner. More importantly, B3-2 exhibited an oral bioavailability of 5.65%, and oral administration of B3-2 showed good antitumor activity in MV-4-11 xenograft models. Furthermore, B3-2 showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Pyrazines
/
Tests de criblage d'agents antitumoraux
/
Leucémie aigüe myéloïde
/
Inhibiteurs de protéines kinases
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Prolifération cellulaire
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Relation dose-effet des médicaments
/
Tyrosine kinase-3 de type fms
/
Antinéoplasiques
Langue:
En
Journal:
Bioorg Chem
Année:
2024
Type de document:
Article
Pays de publication:
États-Unis d'Amérique